A rare JAK2 mutation associated with adult-onset Still's disease and exacerbated vaccine-induced innate immune response.

Abstract

Adult-onset Still's disease (AOSD) is a rare systemic autoinflammatory disorder involving immune dysregulation. The aetiology of AOSD is unknown and considered to be multigenic and possibly involving environmental triggers. Here, we report the identification of the very rare germline variant JAK2R947Q in a patient with AOSD who showed a hyperactive innate immune response after mRNA vaccination. We employed data mining approach of genomic and RNA-seq data, biochemical experiments and AlphaFold 3 (AF3) to analyse the mechanisms underlying the enhanced vaccine-induced IFN transcriptomic responses in the patient carrying the JAK2R947Q variant. Biochemical experiments in Ba/F3 cells demonstrated an enhanced cytokine response of the JAK2R947Q variant. In the AF3 model of JAK2, the arginine (R947) interacts with glutamine (Q534) in the SH2-JH2 linker and mutation to non-charged glutamine could interfere with several interactions at this site. The two children of the AOSD patient also carried the JAK2R947Q variant and displayed an elevated basal immune transcriptome in peripheral blood mononuclear cells but did not present the clinical disease. The JAK2R947Q germline variant identified in a patient with AOSD displays enhanced activation upon cytokine stimulation. Our results also suggest that the vaccine-induced innate immune transcriptome response could be used as benchmark in the functional assessment of genetic variants in key genetic pathways controlling immune response.